This invention relates to an amorphous paroxetine composition suitable as a therapeutic agent for sexual dysfunction and to a process for preparing such composition.
The selective serotonin reuptake inhibitor (SSRI) antidepressants have recently emerged as effective new treatments for patients with premature ejaculation. In general, antidepressants influence more than one neurotransmitter system and have affinity for multiple receptors. This heterogeneity of action produces mixed effects, including those on the sexual response cycle. Sexual dysfunction associated with antidepressants, including delayed and completely abolished ejaculation, has been a subject of numerous case reports, studies, and review articles [for example, J. Clin. Psychiatry 54, 209-212, (1993); J. Clin. Psychopharmacol. 3, 76-79, (1983); J. Clin. Psychiatry Mon. 10, 4-10, (1992); Depression 2, 233-240, (1994/1995)]. Because of the lack of abuse potential, relatively benign side effect profile, and fairly consistent reports of delayed ejaculation, SSRI antidepressants seem to be a safe treatment option for patients with premature ejaculation, especially in cases of failed psychological treatment.
The use of the SSRI antidepressant fluoxetine hydrochloride (PROZAC(copyright)) in this regard has been described in U.S. Pat. No. 5,151,448 to Crenshaw et al. A similar treatment, at a relatively lower dosage of active ingredient, has been described in U.S. Pat. No. 5,276,042 to Crenshaw et al. for the SSRI antidepressant paroxetine hydrochloride (PAXIL(copyright)). Other anti-anxiety drugs such as chlordiazepoxide (LIBRIUM(copyright)) and diazepam (VALIUM(copyright)) are not suitable for the treatment of premature ejaculation.
The preparation of a class of SSRI antidepressants has been disclosed in U.S. Pat. No. 4,007,196 to Christensen et al. In Example 2 of this patent, the preparation of (xe2x88x92)-trans4R-(4xe2x80x2-fluorophenyl)-3S-[(3xe2x80x24xe2x80x2-methylenedioxy-phenoxy)methyl]-piperidine (generic name paroxetine) is described (formula A), 
wherein paroxetine is obtained as a free base then converted to its maleic acid salt. The use of the acetate salt of paroxetine has been described [Psychopharmacology 57, 151-153 (1978); Psychopharmacology 68, 229-233 (1980); European Journal of Pharmacology 47, 351-358 (1978)]. There also has been limited use of the hydrochloride salt in aqueous solution [Acta. Pharmacol. et Toxicol. 44, 289-295 (1979)]. More recently, U.S. Pat. No. 4,721,723 to Barnes et al. has disclosed the preparation of a crystalline paroxetine hydrochloride hemihydrate. However, this particular process requires post-synthetic treatment of the product in order to obtain the crystalline form, which adds to the difficulty and overall cost of production. Amorphous paroxetine hydrochloride has been reported by Barnes et al. to be undesirably hygroscopic.
The present invention provides an economical manufacturing process for the preparation of a substantially non-hygroscopic, free-flowing, amorphous paroxetine hydrochloride-ethanol composition suitable as a therapeutic agent for the treatment of premature ejaculation.
Compositions of amorphous paroxetine hydrochloride and a hydroxyl-bearing compound, as well as methods for production of such compositions are disclosed. The present inventive method generates amorphous, substantially non-hygroscopic paroxetine hydrochloride from a reaction of paroxetine base with a hydrochloric acid/ethanol solution followed by drying of the product. This invention overcomes inherent problems associated with crystallization methods of the prior art, including the recovery of product. The composition embodying the present invention is eminently well suited for the preparation of tablet dosage forms containing paroxetine.
The paroxetine base can be prepared according to the procedure set forth in U.S. Pat. No. 4,007,196 to Christensen et al. Paroxetine hydrochloride solute is obtained by combining an appropriate amount of hydrochloric acid in absolute ethanol with the free base. The amorphous composition is produced upon drying of the product. In a preferred embodiment, the amount of ethanol present in the product is not more than about 10 percent by weight based on the paroxetine hydrochloride. Under this condition, the amorphous composition is a substantially non-hygroscopic solid, thus providing a manufacturing advantage. In a more preferred embodiment, the amount of ethanol present in the composition is in the range of about 1 to about 4 weight percent, based on paroxetine hydrochloride. This amorphous composition is stable and is amenable to incorporation into both tablet and suppository dosage forms.
At least one compound having at least hydroxyl moiety, i.e., an hydroxyl-bearing compound, can be used in addition to, or instead of, ethanol or other monohydric alcohol in making the amorphous paroxetine composition of the present invention. Addition of one or more hydroxyl-bearing compounds to the composition is useful in improving the stability of the amorphous paroxetine composition as measured by color and by paroxetine content. Suitable hydroxyl-bearing compounds are carboxylic acids, hydroxycarboxylic acids, sugar acids, polyhydric alcohols and cyclodextrins. A preferred hydroxycarboxylic acid is citric acid. A preferred polyhydric alcohol is D-mannitol. A preferred cyclodextrin is hydroxypropyl-beta-cyclodextrin.